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MLH1 Gene: Lynch Syndrome

Mutations in the MLH1 gene cause Lynch syndrome.

MLH1- Associated Lynch syndrome:

Men and women with a mutation in MLH1 have a 52-82% lifetime risk (up to age 70) to develop colon or rectal cancer.  Moreover, this syndrome is associated with a 30% risk of a second colon or rectal cancer appearing within 10 years of the first colon cancer. It is important to note that colorectal cancer risk remains higher after age 70.

Women also have a 25-60% lifetime risk for endometrial cancer and 4-13% lifetime risk for ovarian cancer (up to age 70).

People with Lynch syndrome are also at increased risk for other cancers that include cancer of the stomach, urinary tract, ovaries, small intestine, pancreas or bile ducts, sweat glands, and brain.

Individuals with Lynch syndrome also tend to have more precancerous colon polyps that grow faster than individuals without Lynch syndrome. For this reason, anyone with Lynch should have frequent colonoscopies, even if they have several clear colonoscopies in a row.

Several hundred mutations in the MLH1 gene that predispose carriers to colorectal, endometrial and other Lynch syndrome-associated cancers have been found. These mutations may cause the MLH1 gene to stop producing the normal protein, and to produce the wrong protein or no protein at all. When the MLH1 protein is absent or ineffective, the number of mistakes that are left unrepaired during cell division increases substantially. If the cells continue to divide, errors accumulate in DNA and the cells become unable to function properly and may form a tumor in the colon, endometrium or another part of the body.

Mutations in the MLH1 gene are inherited in an autosomal dominant pattern, meaning each first-degree relative, such as sibling or child, has a 50% chance of having inherited this mutation, and genetic testing is recommended for adult relatives.

Mutations in MLH1, when inherited from both parents, cause Constitutional Mismatch Repair Deficiency (CMMRD), a condition that usually presents in childhood and is associated with a high risk of cancer. If both partners have a MLH1 mutation, each child has a 25% chance of inheriting both mutations, which causes CMMRD. For this reason, anyone with an MLH1 mutation who may be having children should have his or her partner tested to see if he or she also carries an MLH1 mutation.

To learn more about Lynch syndrome please visit our Lynch Syndrome group


  1. Aarnio et al. “Cancer risk in mutation carriers of DNA-mismatch-repair genes.” International Journal of Cancer. 1999; 12;81(2):214-8)
  2. Dowty et al. “Cancer risks for MLH1 and MSH2 mutation carriers.” Human Mutation. 2013; 34(3):490-7
  3. Hampel et al. “Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset.” Gastroenterology. 2005; 129(2):415-21
  4. Vasen et al. “MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.” Journal of Clinical Oncology. 2001; 19(20):4074-80
  5. Watson et al. “The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome.” International Journal of Cancer. 2008; 123(2):444-9
  6. NCCN. National Comprhensive Cancer Network Guildelines for colorectal cancer screening. Available online. Registration required. 2016

A Summary of Screening Based on NCCN Guidelines:

Colon and Rectal (Colorectal):  FULL Colonoscopy at age 20-25y or 2-5y prior to the earliest colon cancer if it is diagnosed before age 25y and repeat every 1-2y.
Stomach/Upper GI EGD (to be done at the time of the colonoscopy) depending on center of care. Selected individuals with a family history of gastric, duodenal, or more distal small bowel cancer may have increased risk and may benefit from screening.

Individuals of Asian descent may have increased risk for stomach cancer and may benefit from screening.

If screening is done, consider upper endoscopy with visualization of the duodenum and the time of colonoscopy every 3-5 years starting at age 40. Consider H. pylori testing and treatment if detected.

Uterus (Endometrial) Discuss limitations of endometrial cancer surveillance. Know the signs and symptoms like abnormal vaginal bleeding.

Risk-reducing hysterectomy and salpingo-oophorectomy (RRSO) are options when childbearing is complete or not desired, ideally by age 40. Follow high-risk RRSO protocol for surgery and pathology.

Ovarian  Discuss limitations of ovarian cancer surveillance. Symptoms of ovarian cancer include persistent (>2 weeks) of abdominal bloating, changes in bowel habits, frequent urination, or early satiety.

Risk-reducing hysterectomy and salpingo-oophorectomy (RRSO) are options when childbearing is complete or not desired, ideally by age 40. Follow high-risk RRSO protocol for surgery and pathology.

Bladder and Ureter If there is a family history of bladder and/or ureter cancer, offer surveillance with urine cytology and urinalysis (with micro) every year from age 30, including discussion of benefits and limitations. Routine cystoscopy is not indicated, if the results of these tests are normal.
Central nervous system Consider annual physical/neurological eamination starting at 25-30. No other recommendations have been made.
Pancreatic  Dependent on care center. No national guidelines or protocols. Patients can consider clinical trials and research studies for pancreatic cancer screening.
Breast and Prostate Not enough increase in risk to recommend additional screening at this time.

Aspirin may decrease risk, but optimal dose and duration are uncertain. Talk to gastroenterologist for discussion of personal risks and benefits.

Oral contraceptives lower the risk of ovarian cancer by 50% when taken for 3-5 years and also lower endometrial cancer risk. Depo-medroxyprogesterone acetate (depo Provera) and Levonorgestrol (Mirena) intrauterine system may also be used for endometrial cancer risk reduction.

Avoid Smoking